Studies completed, under way or planned on the target tissue toxicity of anticancer drugs include: a) the development of in vivo models of nephrotoxicity; b) elucidation of the biochemical mechanisms underlying the delayed and progressive mephropathy of MeCCNU; c) characterization and mechanism of the acute nephrotoxicity of high dose chlorozotocin or streptozotocin; d) role of bioreduction in mediating the nephrotoxicity of mitomycin C; and e) comparative studies on the nephrotoxicity of the newer cis-platinum analogs. The initial emphasis has been primarily on nitrosoureas. We have developed a reliable model of MeCCNU renal damage in BDF mice and Fischer 344 rats and have shown that histopathological changes produced by the drug are closely paralleled by marked changes in biochemical parameters measurable in vitro in kidney slices, as well as by certain in vivo renal function tests. The Fischer rat also was shown to be a relevant animal model for studying the nephrotoxicity of other nitrosoureas. For example, high doses of either streptozotocin or chlorozotocin were found to be acutely nephrotoxic, whereas, low doses of chlorozotocin resulted in a chronic progressive nephropathy similar to that of MeCCNU. Unlike MeCCNU, however, chlorozotocin lacks carbamylating activity suggesting that the nephrotoxicity of the nitrosoureas is a result of the alkylating capabilities of the compounds. The overall goals of the studies are to: a) elucidate the chemicobiologic events that underlie the nephrotoxicity of the nitrosoureas and b) develop improved methods of predicting, monitoring or treating such reactions in patients.